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      Progranulin Mediates Caspase-Dependent Cleavage of TAR DNA Binding Protein-43

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          Abstract

          TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene ( PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate ∼35 and ∼25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          26 September 2007
          : 27
          : 39
          : 10530-10534
          Affiliations
          [1] 1Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224,
          [2] 2Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida 33612,
          [3] 3International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy, and
          [4] 4Division of Regenerative Medicine, University of Manchester, Manchester M13 9PT, United Kingdom
          Author notes
          Correspondence should be addressed to Dr. Leonard Petrucelli, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. petrucelli.leonard@ 123456mayo.edu

          *Y.-J.Z. and Y.-f.X. contributed equally to this work.

          Article
          PMC6673167 PMC6673167 6673167 3271422
          10.1523/JNEUROSCI.3421-07.2007
          6673167
          17898224
          aec59c25-cde4-4875-8f1b-294354de4c71
          Copyright © 2007 Society for Neuroscience 0270-6474/07/2710530-05$15.00/0
          History
          : 27 July 2007
          : 15 August 2007
          : 15 August 2007
          Categories
          Articles
          Brief Communications
          Custom metadata
          true
          neurobiology-of-disease

          caspase,progranulin,frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U),apoptosis,amyotrophic lateral sclerosis (ALS),TDP-43

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